Chronic hepatitis B virus (HBV) infection is a persistent, potentially progressive necroinflammatory liver disease associated with chronic HBV infection. Worldwide about 240-400 million persons are chronically infected with HBV, and chronic HBV infection is a major global cause of severe liver morbidity and liver-related mortality (Hepatitis B Factsheet, World Health Organization, 2013; Hoofnagle J H, et al., Management of Hepatitis B: Summary of a Clinical Research Workshop, Hepatology, 2007, 45(4):1056-1075; EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection, J. Hepatology, 2012, 57:167-185 (EASL 2012); Lesmana L A, et al. Hepatitis B: overview of the burden of disease in the Asia-Pacific region, Liver International, 2006, 26:3-10; Lok A S F and McMahon B J, Chronic Hepatitis B: Update , Hepatology, September 2009:1-36 (Lok 2009)).
The chronic state of HBV infection in individual subjects was traditionally established by confirmation of persistent detectability of hepatitis B surface antigen (HBsAg) in subject serum for 6 months or more. The U.S. Center for Disease Control (CDC) considers a serologic profile consistent with chronic HBV infection to be: HBsAg-positive and HBsAb-negative, with detectable IgG antibody to heptatits B core antigen (IgG HBcAb) and non-detectable IgM antibody to heptatits B core antigen (IgM HBcAb). In such individuals, serum hepatitis B e antigen (HBeAg) can be detectable or non-detectable and is more likely to be detectable at later stages of chronic HBV infection.
Current regulatory-approved therapies for chronic HBV infection include parenterally-administered alpha-interferons (non-pegylated or pegylated) and various orally-administered nucleoside/nucleotide (nucleos(t)ide) inhibitors of the HBV polymerase/reverse transcriptase (HBV Pol-RT)). Each of these agents have suppressed HBV replication and induced HBeAg loss/seroconversion in only about 20-35% of HBeAg-positive patients after a year of treatment (EASL 2012; Lok 2009; Sorrell M F et al., National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis B, Ann Intern Med, 2009, 150(2):104-110; Woo G et al., Tenofovir and Entecavir Are the Most Effective Antiviral Agents for Chronic Hepatitis B: A Systematic Review and Bayesian Meta-Analyses, Gastroenterology, 2010:1-17). Although patients with chronic HBV infection who are HBeAg-positive experience up to 30-35% loss of HBeAg under current 48-week treatment regimens with pegylated interferons (PegIFNs), within 2-5 years after treatment 20-50% of patients have regressed to their original HBeAg levels (Perillo R, Benefits and Risks of Interferon Therapy for Hepatitis B, Hepatology, 2009, 49:S103-S111). Thus, current HBV therapies can provide prolonged suppression of HBV replication, but most patients fail to achieve responses that are durable post-treatment.
In contrast, suppression of HBV replication to low or non-detectable levels can be maintained for longer periods in most patients continuously treated with potent HBV nucleos(t)ides, with or without HBeAg loss or seroconversion, but such prolonged periods of nucleos(t)ide treatment are associated with risk of tolerance, viral resistance, and patient compliance difficulties (Chotiyaputta W et al., Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis B, J. Hepatology, 2011, 54:12-18; Lee M and Keeffe E B, Study of adherence comes to the treatment of chronic hepatitis B, J. Hepatology, January 2011, 54(1):12-18; Scaglione S J and Lok A S F, Effectiveness of Hepatitis B Treatment in Clinical Practice, Gastroenterology, 2012, 142:1360-1368).
With the continued worldwide prevalence of HBV-associated mortality and severe morbidity, there remains a need for improved HBV antiviral therapies that can achieve sustained viral response during and after treatment.